Serotonin antagonists



1 2,995,567 SEROTONIN ANTAGONISTS Lewb H. Sarett, Princeton, Edward F. Rogers, Mlddletown, and Robert L. Clark, Woodhridge, NJ, assignors to Merck 8: Co lne., Rahway, N..l., a corporation of New Jersey No Drawing. Filed Sept. 4, 1957, Ser. No. 681,904 '1 Clalms- (Cl. 260-319) This application is a continuation-in-part of our copending application Serial #648,782, filed March 27, 1957, now abandoned.

This invention relates to tryptamine compounds and more particularly to tryptamine compounds having activity as serotonin antagonists.

Serotonin is widely distributed throughout the body in. man and other mammals. .The physiological activity of serotonin and the action of serotonin antagonists are 1 discussed in J. Am. Med. Assn, 161, 460-461 (1956). As indicated in this article, Woolley and Shaw have suggested that the presence of serotonin is essential to norand mental disorders may result from serotonin deficiency. Serotonin is a vasoconstrictor, however, and excessive amounts in the blood stream appear to be responsible for various peripheral side effects, including high blood pressure. Administration of a serotonin antagonist counteracts the harmful peripheral side effects without interfering with the beneficial action of serotonin on the central nervous system.

According to the present invention new tryptamine-derivatives having far higher serotonin antagonist activity than previously known compounds are prepared.

The compounds of the present invention have the 'gen eral formula mal mental processes;

R40 CllsCHsN l N CH:

and the acid addition salts thereof. In this formula R is selected from the group consisting of hydrogen and lower alkyl radicals, R, and R, are selected from the group consisting of hydrogen and R is selected from the group consisting of hydrogen and lower .alltyl, arallryl, lower allcanoyl, aroyl, and aralkanoylradicals; and n is a positive integer having the value of either 1 or 2.

The compounds according to the presentinvention may be divided into four groups, depending on the radical attached to the -position of the indole nucleus. These groups are (l) the S-hydroxyindoles (R =H), (2) the 5- acyloxyindoles (R is a lower alkanoyl, aroyl, or aralkanoyl radical), (3) the S-alkoxyindoles (R, is a lower alkyl radical), and(4) the S-benzyloxyindoles (R is the benzyl radical). The S-hydroxyindoles and the S-acyloxyindoles generally are more active than the corresponding S-alkoxyindoles, although the latter also display serotonin antagonist activity. The S-benzyloxyindoles are of value as intermediates in the formation of the corresponding 5- hydroxyindoles.

Examples of compounds which may betonned according to the present invention include lower alltyl radicals,

United States Patent. O

, 2,995,567 Patented Aug. 8, 1961 ice . 2 l-(4'methoxybenzyl)-2-methyl-3-(2-aminoethyl)-5- I hydroxyindole,

l-(4'-hydroxybenzyl)-2-methyl-3-(2-aminoethyl)-$- hydroxyindole, s l (4-methoxybenzyl)-2-methyl-3-(2dimethylamin0ethyl)- S-hydr'oxyindole, 1 l-(4-methoxybenzyl)-2-methyl-3-( Z-aminoethyl -5- scetoxyindole, l-(4-methoxybenzyl)-2-methyl-3-(2-dimethylaminoethyl)-S-acetoxyindole, 1-(4-methoxybenzyl)-2-methyl-3-(2-dimethy1aminoethyl)-5-isobutyroxyindole, l-(4-methoxybenzyl)-2-methyl-3-(2-aminoethyl)-5- benzyloxyindole, l-(d-methoxybenzyl)-2-methyl-3-(2-aminoethyl)-5- phenylaeetoxyindole, 1- (4-methoxybenzyl)-3-(2-aminoethyl)-5-methoxyindole,

responding to the above general formula are also within the scope of this invention.

Various processes may be used to make the compounds of the present invention. Three processes which applicants have found particularly desirable will be illustrated.

Each of these starts with an city-substituted phcnylhydrazine of the general formula moQ-mmm or an acid addition salt thereof, where R, is either a lower alkyl radical or the bcnzyl radical. The acid addition salt may be the hydrochloride, sulfate, acetate, or the like. The compound-p-benzyloxyphenylhydrazine is the usual reagent for preparing indoles having a benzyloxy,

hydroxy, or acyloxy substituent in theS-position. This.

compound may be prepared as described by Mentaer, Beaudet, and Bory, Bull. Soc. Chim.. (France), pages 421-423 (1953). The compound =p-methoxyphenylhydrazine which is useful in preparing S-methoxyindoles, may be prepared as described in Blaikie and Perkin, J. Chem. Soc. (London), volume 125, pages 296-313 (1924). Other phenylhydrazine reagents can also be made according to these procedures.

The first process, which is useful for making primary, secondary, or tertiary tryptamines, proceeds as follows:

moGmmm (I!) ltmon-Q-omnu u (III) n.)- (1v) lomoocmcmcnix of) mo cmculx CHI N (1H1 v (1) EN\ Bl 1 mo HtcHsN\ -HCl 81 H: N I in.

iono- (vtn In the above equation R R R R and n are as defined above; and both Hal and X are either chlorine or bromine. i.e. halogen having an atomic weight in the range of 35 to 80. The halogens represented by Hal and X may be but are not necessarily identical.

The aralkyl halide reagent (III) has either one or two orgy substituents attached to the ring. The oxy sub stituents may be either alkorty or aralkoxy groups. Preferred aralkyl'halidcs are those having a single alkoxy or aralkoxy substituent attached to the para position. Examples of suitable reagents are 4-methoxybenzyl chloride, 4-benzyloxybenzyl .chloride, 3,4-dimethoxybenzyl chloride, and the corresponding bromides.

The benzylation of the substituted phenylhydrazine compound, represented as the first step in the above equation, may be carried out following the procedure of Audrieth et 1941), or according to the Audrieth procedure as modtfied by Shaw, 1. Am. Chem. Soc., volume 77, page 4319 The second step in'this process consists in condensing the product of the first-step with a methyl gammahalopropyl ketone (V), which may be either $-chloropentanone-2 or 5-bromopentanone-2. The condensation is carried out in an acidic medium using a solvent such as ethanolic hydrogen chloride orglacial acetic acid. While these solvents are preferred, other acidic solvcntssuch as ethanolic sulfuric acid and the like are also suitable. The reaction is carried out at elevated temperature such as reflux temperature. The resultingproduct is a haloalkyl indole (VI).

The next step of the reaction is to aminate the halonlkyl'indole (VI). Ammonia. a primary amine, or a secondary amine is used for this purpose depending on al., I. Org. Chem., volume 6,-page 41:1

' such as the hydrochloride, sulfate, or acetate.

- 4 whether the product desired is" a primary, secondary, or tertiary tryptamine. Suitable primary amines include methylsmine, ethylarnine, and the like. Secondary amines include dimethylamine, diethylamine, methylethyl amine, and the like. This reaction may be carried out at elevated temperature such as reflux temperature, or in a bomb, or at room temperature for an extended length of time.

The product (VII) may be recovered either as the free tryptamine compound or as an acid addition salt thereof, Generally it is preferred to recover the compound in the form of an acid addition salt.- The acid addition salts may be easily prepared from the corresponding tryptamine compounds by conventional acidification proced urcs.

All of the compounds defined by Formula V-II also fall within the scope of Formula I, although the converse is not true. Compounds VII are useful as serotonin antagonists or as intermediates for conversion to serotonin antagonists. depending on the nature of the group attached to the 5-position.

The S-alkoxyindoles conforming to Formulas I nnd VI! are useful as serotonin antagonists. The S-benzyloxyindoles'represented by Formulas I and VII are convertible to the corresponding novel S-hydroxyindoles and S-acyIoxyindoIes, which are potent serotonin antagonists included within Formula I (but outside VII), as illustrated by the following equation:

rm ---0 mt um ion").

In the above equation R. is a lower alkyl, aryl. or aralkyl radical and R R,, 11,, and n are as previously defined. The hydrogenation illustrated above is carried out by conventional means such as reaction with hydrogen under superatmospheric pressure in the presence of a suitable'eatalyst such as palladium on charcoal.

The esterification of the S-hydroxy radical in primary and secondary tryptamines is accomplished by saturating ilCl a suitable solvent such as glacial acetic acid with hydrogen chloride, adding the S-hydroxyindole to this solution,

MGM

cmooomcmcnm (VIII) -cthctr,

CIT: C0

omrm' (in) co mo 0mm cn. co 4 in i x 1:,0- --\--cn,o u,mr,

0R1)- (XI) The phenylhydrazine reagents (II) are the same as those used in the first process. Phthalimidopentanone- (VIII) may be prepared by condensing-S-chloropentanone-2 with potassium phthalimide or with phthalimide in the presence of potassium carbonate. The best procedure known to applicants. for carrying out this condensation is as follows.

A mixture of 29.4 g. of phthalimide, 37 g. of potassium carbonate and ISO ml. of dimethylformamide is stirred and heated at 95 C. for one hour. After cooling the mixture to 60 C., 16.2 g. of S-chloropentanone- 2 is added and heating at 95 C. continued for one hour. The reaction mixture is then cooled to 15 C. and poured into 200 ml. of chloroform. A mixture of ml. of 30% caustic in 400 ml. of ice cold water is then added,

the mixture stirred, and the chloroform layer separated. The aqueous layer is extracted with two portions of ml. and 60 ml., respectively, of chloroform and the combined chloroformextracts washed with two 200-ml. portions of 0.25 N sodium hydroxide to remove phthalimide, and then with 200 ml. of water. The chloroform is then dried over magnesium sulfate and concentrated in vacuo to an oil. Crystallization is induced by cooling and trituration with water. After crystallization has started. a total of 25 ml. of water is added. After aging at 5 C. for several hours, the product S-phthalimitlopentanone-Z is filtered, washed with two l5-ml. portions of water and two l5-ml. portions of petroleum ether, and air-dried at 50' C.

The phcnylhydrazine reagent (II) and S-phthalimidopentanone-Z are condensed in an acidic medium. Suitable solvents for this medium include ethanolic hydrogen chloride, glacial acetic acid, and the like. The reaction is carried out at elevated temperature, such as reflux temperature. The product (IX) is an indole having a phthalimidoalkyl side chain attached to the 3- position as indicated in the above equation. Among the indoles which may be thus formed are 2-methyl-3-(2- phthalimidoethyl) S methoxyindole, 2 methyl 3 (2- hthalimidoethyl)-S-bcnzyloxyindole, and 2-mcthyl-3-(2- phthalimidopropyl)-5-methoxyindole.

The phthalimidocthyl indole (IX) is reacted with an oxy-substituted benzyl halide- (III) as indicated in the above equation. The suitable substituted'benzyl halides are the same as in the first process. This reaction is carried out in an inert organic solvent suchas dimcthylformamide using a suitable condensing agent such as sodium hydride or sodium amide. This results in the formation of compound (X) having an oxy-substituted benzyl radical attached to the nuclear nitrogen atom.

The next step in this process is to remove the phthalimido group by reaction with hydrazine. The hydrazine is generally in the form of the monohydrate. This yields a primary tryptamine compound (XI) having serotonin .antagonistactivity. The primary tryptamines .(XI) have the same general formula as the tryptamines (VII) described in the first method-except that R, and R; must be hydrogen.

Tryptamines (XI) having a S-benzylbxy radical may be converted to the corresponding S-hydroxyor S-acyloxytryptamines as described previously.

A third general method for making compounds according to this invention is similar to the second general method except for some rearrangement in the order of steps. This method may be represented by the following equation:

IMO-QNHNH:

(BM) a camel in) mo-NNm CHeCOCHgC H3O HN (VIII) em). (x)

l (ills Allof the reagents are the same in the second and third methods.

8 (C) I-(4-merlioxybenzyl)-2-merhyl-3-(2-anunoethyl)J- melhoxyindole hydrochloride Q A 4-gram portion of l-(4-m'ethoxybenzyl)-2-methyl-3- (Z-phthalimidoethy'l)-5-methoxyindole was dissolved in 100 ml. of absolute alcohol and the solution heated. To the hot solution 1.5 ml. of 95% hydrazine hydrate was 7 added with stirring. The solution was refluxed, becoming red and gradually turning yellow. Refluxing was continued for one andone-half hours and a precipitate began to form after about one-half hour. The refluxed mixture was cooled and 25 ml. of water and ml. of

Thediflerence in the two methods lies in the different order in which the steps'of the reaction are carried out.

The invention will now be described with reference to specific'embodiments thereof.

v 4 EXAMPLE I (A) 2-merhyl-3 (L 'IuhQIIrnIdoeIhyIFS-rhethaxyindole To a solution of 10 of 4-methoxyphenylhydrazine in 300 ml. of 2.3 N ethanolic hydrogen chloride were added 16.8 g. of S-phthalimidopentanone-Z. This mixture was heated under reflux with stirring for about one hour.

About 100 ml. of ethanol were removed in vacuo,

ml. of water were added and the mixture cooled. A precipitate of 2-methyl-3 -(ZphthalimiddethyI)-5-mcthoxyindole formed. This was removed by filtration and washed with two 25-ml. portions of water. "The product was dissolved in warm acetone, using about 10 ml. of acetone per gram of product. and precipitated by the addition of about 6 ml. of water per gram. Yield about 87%; MP. l82-l83- C.

(B) Preparation of l-(d-rnclhoxybenzyl)-2-me!hyl-3- (Z-phthalimidOethyl)-5-methoxyind0le To a cooled, well-stirred mixture of l g.of a 50% emulsion of sodium hydride and .40 ml. of dry dimethylformamide was added 6.8 g. of 2-methyl-3-(2-phthalimidoethyl)-5-methoxyindole. After stirring at 20 C. for one and one-half hours, the mixture was cooled to 0 C., and 3.12 g. of 4-methoxybenzyl chloride was gradually added. After 40 minutes the solution was allowed to warm to room temperature overnight. and cooled. Gradual additio'n of 100 ml. of water caused crude l (4 methoxybenzyl)2-mcthyl-3-(2-phthalimidocthyl)-5-methoxyindole to precipitate as a gum. The liquidwas decanted and the gummy product was dissolved in 25ml. of acetone.' Addition of 20 ml. of water precipitated a purified product. which was recrystallized from absolute alcohol. Yield about .40%;'M.P. l3l- 132 C.

Amlysis.Calculated for c n ons: C, 73.98%; H, 5.77%; N, 6.16%. Found: C, 74.13%; H. 5.72%; N, 6.32%.

acetic acid were added. A precipitate of phthalyhydrazine was removed by filtration. The alcohol was removed in vacuo from the filtrate. This resulted in formation of an additional quantity of phthalyhydrazide. which was filtered oil. The filtrate was made basic and extracted several times with ether. The ether solutions were combined and alcoholic hydrogen chloride was added until the solution was acidic. The solution was cooled overnight and l-(4-methoxybenzyl)-2-methyl-3- (Z-aminoethyI)-5-methoxyindole hydrochloride was removed by filtration. This material was recrystallized from absolute alcohol. Yield 85%; MP. l94'-l97 C. Analysis. Calculated for CgoHgNgOgHCII C, 66.56%; H, 6.98%. Found: C, 67.02%; H, 6.75%.

EXAMPLE 2 (A) I-(3,4-dimethoxybenzyl)-2-merhyl- (Z-phthalimidoethy!)-5-mcthoxyind0le The procedure of Example 1, stepC, was followed except that l-(3,4-dimethoxybenzyl)-2-methyl-3-(2-phthalimidoet'hyl)-5-methoxyindole was the reagent. The product was l-(3,4-dimethoxybcnzyl)-2-methyl-3-(2- amino'ethyl)-S-mcthoxyindole hydrochloride. The pure product was crystallized from absolute ethanol; MI. 186'-187 C.

AnaIysis.-Calculated for C H N O Cl: C, 64.51%; H, 6.96%. Found: C, 63.86%; H, 7.08%.

EXAMPLE 3 (A) I -(4-me1hoxyph enyl) -I-(4-methoxybenzyl hydrazine hydrochloride To a mixture of 13.5 g. of 41% sodium hydride emulsion and ml. of dry dimethylformamide was added a solution of 27.6 g. of 4-methoxypheny1hydrazine in 60 ml. of dry dimethylformamide. The solution was stirred for one and one-half hours and then cooled to- 0' C., and 35 g. of 4-methoxybenzyl chloride were added slowly. The mixture was thenstirred' at room temperature for 15 hours. The gradual addition of 400 ml. of water caused 1-(4-mcthoxybenzyl) 1 (4-methoxyphenyl)-hydrazine to separate as an oil. This was separated and the aqueous layer was extracted with three SO-ml. portions of chloroform. The combined chloroform extracts were washed and dried. The chloroform was evaporated in vacuo at a temperature under 40 C. The residue was dissolved in 30 ml. of absolute alcohol. To this solution 30 ml. of 3 N hydrogen chloride in. absolute alcohol were added. This caused precipitation of H4- methoxybenzyl)-l-(4-methoxyphenyl)hydrazine hydrochloride. The product was recrystallized from an ethanol-ether mixture. Yield 65%; MP. -l63 C.

.room temperature for 6 days.

Analysis. Calculated for CxsIIlBNQOQ'HC]: C.

61.11%; H, 6.50%; N, 9.51%. Found: C, 61.27%; H, 6.76%; N, 9.41%.

3) 1-(4-melhoxybenzyl)-2 methyl-3-(Z-chloroethyD- -rm'lhoxyimlole A mixtureof 5.0 g. of l-(4-methoxybcnzyl)-1-(4-' methoxyphenyl)hydrazine hydrochloride. 30 m1. of glacial acetic acid and 2.4 ml. of S-chloropentanone-Z was heated on a steam bath. The temperature rose to above 95 C. and then the reaetionmixture cooled to about 85 C. The mixture was then heated for an additional 20 minutes 'on the steam bath. the solution was removed, and ml. of water was added. The crude solid which separated was recrystallized from 30 ml. of

' absolute alcohol to give 1-(4-methoxybenzyl)-2-methyl- 3-(2-chlorocthyl)-5-methoxyindole. Yield 3.8 g.; M.P. 99-l03 C.

Anulysis.Calculated for C l-l NOfll: C, 69.85%; H, 6.45%. Found: C. 70.65%; H. 6.97%.

(C) -(4nu'!h0.\'y hcnzyl -2-me!hyI-3-( 2-ethylamt'rtoethyl -5-melhoxyimlolc hydrochloride A mixture of 5 g. of l-( 4-methoxybenzyl)-2-methyl-3- (Z-chloroethy'l)-5-methoxyindole and 50ml. of anhydrous cthylamine was heated in a bomb at 100 C. for 24 hours. The excess ethylamine was removed and the residue dissolved in ether, washed, dried, and dry hydrogen chloride added. A precipitate of 1-(4-methoxybenzyl)-2-methyl- 3-'( 2 ethylaminoethyl -5-methoxyinole hydrochloride was 1 recovered. The product was recrystallized from alcohol- Analysir.'Calculated for c ir,',i-t,0,-Hct= C; 67.94%;11, 7.51%; N, 7.20%.v Found: C, 67.88%; H, 7.48%; N, 7.51%.

EXAMPLE 4 (A) I 4-me1hoxybenzyl )-2-mcthyl-3-(2-isopropylaminoe'thyl)-5-melh0xyindole hydrochloride A solution of. 4 g. of 1-(4-methoxy benzyl)-2-methyl-3- (2-chloroethyl)-5-mcthoxyindole prcparedas described in Example 3, in 5.0 ml. of isopropylamine, was heated in a bomb at 100 for 24 hours. Some isopropylaminc hydrochloride was removed by filtration. The filtrate-was evaporated. Sodium hydroxide was added to the residue which was then extracted with ether. The ether layer was washed, and dried and dry hydrogen chloride added. The product l-(4-nicthoxyhcnzyl)-2-methyl 3 (Z-isopropylaminoethyl)-5-mcthoxyindolc hydrochloride separated. It was crystallized from ethyl acetate by theaddition of ether, M1. 147-149.

Anulysis.-Calculatcd [or 68,55%; H, 7.74%; N, 6.95%. 7.89%; N, 6.80%.

EXAMPLE 5 1-(4-mcrlmxybenzyl)-2-meIhyl-3f(2-dlmethylamin0- ethyl) -5-meth0xyind0le hydrochloride.

10 EXAMPLE 6 (A) l-(4-methoxybenzy!)-l (4-benzylphenyl) hydrazine hydrochloride To a well-stirred suspension of 11.2 g. of 50% sodium hydride emulsion in ml. of dry dimethylforrnamide were slowly added 39 g. of 4-bertzyloxypheriylhydrazine in 100 ml. of dimethylformamide. After stirring for 45 minutes the mixture was cooled and Y36 g. of 4-methoxy benzyl chloride slowly added. The temperature was gradually allowed to warm up to room temperature and the mixture stirred 12. hours. Over a period of about one hour, 420 ml. of water were added, and a solid was precipitated. This was dissolved in about 1.5 liter of ether, washed with. water, dried. and alcoholic hydrogen chloride was added. A dark oil separated which solidified almost immediately. It was crystallized from about 350 ml. of methanol by the addition of 1.5 liters of ether. Yield 29 g. A small amount of the product was recrystallized; M.P. 182-183- C.

Ana1ysis.-Calculated for c tt mo ttcu 68.01%; H, 6.25%. Found: C, 67.71%; H, 6.09%.

A mixture of 3.4 g. of 1-(4 methoxybenzyl)-1-(4benzyloxyphenyU-hydrazine hydrochloride, 2.3 g. of 5- phthalimidopentanone-Z, and 25 m1. of glacial acetic acid was heated on a steam bath to a maximum temperature "of'100 C. for-20 minutes. After cooling 25ml. of water (C) l.-(4-metlmxybenzyl)-2-methyl-3-(2 amin0e!hyl)- S-bcnzyloxyindole hydrochloride To a hot stirred solution of 4 g. of 1-(methoxybenzyl )-2-methyl-3-(Z-phthalimidoethyl)-5 bcnzyloxyindole in ml. of methanol was added 3 ml. of hydrazine hydrate. The solution was heated under reflux for three hours. The solvents were removed in vacuo until considerable precipitate had separated. After adding 20 ml. of water and 10 ml. of acetic acid. the remaining precipitate was removedby filtration. The filtrate was evaporated in vacuo until an oily precipitate began to separate. At this time ether and sodium hydroxide were added and the basicsolution and precipitate extracted with ether several times. The combined ether extract was washed, driedand alcoholic hydrogen chloride added to precipitate a gelatinous precipitate of l-(4-m ethoxybenzyl)-2-methyl-3-(2- arninoethyl)-5-benzyloxyindole hydrochloride. This was crystallized from .10 ml. of methanol by the addition of 30 ml. of ether. Yield 1.5 g.; MP. 196-'-198 C. Further recrystallization raised the melting point to 203 Analysis-Calculated for 11.45%;11, 6.69%.

Found: C, 71.40%; H, 6.68%.

(D) I-(4-mcth0xybvnzyl)-2merhyl-3 (2-amin0ethyl) 5-hydr0xyindole hydrochloride" benzyl)-2-methy1-3-(2-arninoethy1)-5 -hydroxyindole hydrochloride. Yield 75%; M.P. 25.7 '-254' C.

- 1 1 Iv Analysis.--Calcul ated v for C li l ljo HCl: 65.80%; H, 6.68%. Found: C, 65.85%; H, 6.47%.

(E) I-(4 methoxybrnzyl)-2-mclhyl-3 (2-amin0ethyl)-5- mctoxyimlole hydrochloride A solution of 4 ml. of glacial acetic acid was saturated with hydrogen chloride. The 0.5 g. of l-(4-methoxy-- benzyl)-2-methyl-3-(2-aminoethyl)-5-hydroxyindole hy- Andl vsis.----Calculatcd for c,,tt,.N,o,-uc|= c, 64.85%; H. 6.48%.- Fotmd: C, 65.23%; H, 6.44%.

EXAMPLE 7 -A mixture of t of t- (4-methoxybenzyl)-2-methyl- 3-(Z-aminoethyl)QS-methoxyindOIc hydrochloride made as described in Example 1-0, and 7.0 g. of-pyridinc hydrochloride was heated to 200 C. for minutes. The dark solution was cooled, diluted with'water and neutralized with sodium bicarbonate. 'An oil separated and was dissolved in'sodium hydroxide. This solution was made acidic with'carbon dioxide and the solution filtered. Ammonium hydroxide was added to-the filtrate and a. solid separated, M.P. about 155 C. This was 1-(4- hydroxybenzyl) 2 methyl-3-(2-aminoethyl)-5-hydroxyindole.

EXAMPLE 8 (A) I -(4-methoxybenzyl) -2-methyl-3-(2-chloroelhyl) -5- v benzyloxyin dole" I i A mixture of 6 got l-(4-methoxybcnzyU-l-(4-bctt2t't oxyphcnynhydrazine' hydrochloride. prepared as described in Example 3. 30 ml. of glacial acetic acid, and 2.8 ml. of Schloropcntanone-Z was heated on a steam bath. The internal temperature rose to 102 to 104 C. After 30 minutes the mixture was cooled and 10 ml. of water added. A black oil separated and crystallized on standing for about l6 hours. The product l-(4-mcthoxybenzyl)- 2-mcthyl-3-(2-chl0rocthyl)-5-bcnzyloxyindole was recrystallized from ml. of absolute alcohol. Yield 6.7 g.; M.P. 65 to 67 C. i

- Analy'sis.-Calculatcd for Q H gNO CI-HCI: 74.35%; H, 6.24%. Found: c, 74.56%; H, 6.15%.

- (B) I -(4-merh0xybenzyl)-2-methyl-3-(2-dimethylamlnov ethyI)-5-benzyloxyindole hydrochloride This precipitate was recrystallized from 15 ml. of absolute alcohol by the addition of ether. 133" to 136 c.

Analysis. Calculator! for C H N O 'HCI. C, 72.31%; H, 7.15%. Found: C. 72.l0%; H, 7.00%.

(C) l- (4-methoxybcnzyl -2-mcthyl-3-(2-dimethylaminoethyl)-5-hydroxyirtdolc hydrochloride A solution of 4.6 g. of 1 -(4-methoxybcnzyl)-2-methyl- Il-(Z-dimethylaminocthyl)-5-bcnzyloxyindole hydrochloride in ml. of methanol was hydrogenated at 40 p.s.i.g.

Yield 4.5 'g.; M.P.

in the presence of l g. of 5% palladium on charcoal as a catalyst. The catalyst was removed, and the reaction mixture concentrated. The product l-(4-mct'hoxybenzyl)-2methyl-3-(2-dimethylamino ethyD-S-hydroxyindole hydrochloride crystallized upon concentration. Yield 1.5 g.; M.P.'258 to 259 C.

Analysis. Calculated for C H N O -HCL C. 67.12%; H, 7.24%. Found: C, 67.36%; H, 7.20%..

(D) I -(4-mctho.rybenzyl )#2-methyl-3-(idimethylamirioethyl) -5-ncet0xyind0le hydrochloride Analysis. Calculated for CzgHuNgOs'HCli 66.26%;11, 7.0l%. Found: C, 66.2l%; H, 6.90%.

EXAM P e 9 1-(4 mcthoxybcnzyl) 2 methyl-3-(Z-dimethylamihoethyl)-5-isobutyroxyindale hydrochloride 1 A mixture of 800 mg. of l-(4-methoxybenzyli-2- methyl-34Z-dimethylaminoethyl)-5-hydroxyindole hydrochloride preparedvas described in Example 8-C, and 10 ml. of isobutyric anhydride was heatedunder reflux for 15 minutes. The reaction mixture was filtered, using a diatamacoous filter aid. Ether was added to the filtrate to precipitate the product 1-( 4-methoxybenzyl) -2-methyl- 3-(2-dimethylaminocthyl -5-'sobutyroxyindole hydrochloride. Yield 800 mg.; MP. to 132 C.

Analysis. Calculated for c fl gmo ucti c. 67.33%; H, 7.68%. Found: c, 67.31%; H, 7.45%.

While the present invention has been described in detail with reference to specific embodiments thereof, it is understood that variations may be made without departing from the spirit of this invention. Accordingly the scope of this invention is to be measured by the scope of the appended claims.

What is claimed is:

1. A compound selected from the group consisting of compounds of the formula R: CIIICIhN 7 13 I 14 5. A min-toxic acid addition salt of l-(4methoxy- References CKcd in the file of this patent bcnzyl )-2-melhyl-3-( 2-aminocthyl -5-hydroxyindole. UNn-ED STATES PATENTS 6. A non-toxic acid addition salt of l-(4-mcthoxy-' bcnzyl)-2-mcthyl-3-(2-aminocthyl)-5-acetoxyindolc. Specter 1958 5 OTHER REFERENCES 7. A non-toxic acid addition salt of l-(4-mclhoxybenzyl) 2 mcthyl-3-(2-dimelhylaminocthyl)-5- accloxy- Wilkins: NewEng. Journ. of Med., Vol. 255, #3, page indolc. 117 (1956). 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA 